(367f) Model Predictive in Vitro Dissolution Testing for Real-Time Release in Pharmaceutical End-to-End Integrated Continuous Manufacturing: An Equivalence Study

The real-time release testing (RTRT) is one of the important cornerstones to achieve end-to-end continuous manufacturing in the pharmaceutical industry. Beside many innovative chemometric model-based process analytical technologies (PAT) to infer the critical quality attributes (CQAs) of drug product, mechanistic model-based predictive testing for target product profiles (TPPs) is also emerging rapidly in the past decade, e.g., tablet dissolution profile [1]. In this study, a predictive mathematical model for tablet dissolution was developed and implemented in an end-to-end integrated continuous manufacturing pilot plant at CONTINUUS to produce immediate release tablets with the specific Extrusion-Molding-Coating (EMC) unit operation. Within the EMC, the active pharmaceutical ingredient (API, a hydrochloride salt) particles are dispersed in the melted polymeric excipients [2]. The model development considered the unique dissolution mechanism of the EMC tablets, which was mainly controlled by the swelling and eroding of the polymeric matrix due to liquid penetration. The major governing equations of the mechanical model consisted of the dissolution, diffusion, and population balance of API particles in the swollen polymeric matrix, as well as the mass balance of API solute in the buffer solution. During in-line implementation, PAT tools, such as laser diffraction for API particle size distribution and near infrared spectroscopy for tablet dosage strength, were OPC connected to the computational server as model inputs. The model output of dissolution time of 70% total API in the tablet was sent to the control system for process monitoring and facilitating the decision-making of real-time release. More importantly, an equivalence study of the model-based predictive dissolution testing was conducted by comparing the model prediction to the experimental dissolution profiles conducted according to USP42-NF37General Chapter <711> Dissolution. Similarity factor f₂ values of >50 were obtained for two levels of drug dosing. A f₂ value of >50 indicates the similarity between the predicted and experimental dissolution profiles. Sensitivity of the model parameters and risk analysis of the model-based dissolution testing were also investigated in this study. Last but not the least, the developed predictive dissolution testing strategy is not limited to the specific API and can be generalized to other APIs for RTRT implementation using the EMC technology.

References:

[1] Zaborenko N, Shi Z, Corredor CC, Smith-Goettler BM, Zhang L, Hermans A, Neu CM, Alam MA, Cohen MJ, Lu X, Xiong L, Zacour BM. First-principles and empirical approaches to predicting In Vitro dissolution for pharmaceutical formulation and process development and for product release testing. The AAPS Journal. 2019; 21:32.

[2] Hu C, Testa CJ, Wu W, Shvedova K, Shen DE, Sayin R, Halkude BS, Casati F, Hermant P, Ramnath A, Born SC, Takizawa B, O’Connor TF, Yang X, Ramanujam S, Mascia S. An automated modular assembly line for drugs in a miniaturized plant. ChemComm. 2020; 56: 1026-1029.